Chemistry of 6-chromanols



United States Patent 3,153,053 CHEMHSTRY OF 6-CHROMANOLS Charles D.Robeson and Donald R. Nelan, both of 755 Ridge Road W., Rochester, N.Y.

No Drawing. Original application Apr. 26, 1962, Ser. No. 1%,249. Dividedand this application Jan. -17, 1963, Ser. No. 258,941

- 8 Claims. (Cl. 26tl-345.5)

i This invention relates to the chemical arts. More particularly, itrelates to that branch of organic chemistry having to do with chromanesand specifically 6-chro manols.

, -6-chromanols, sometimes called 6-hydroxychromanes, are organicchemical compounds having a molecular structure according to the generalformula:

wherein each R is a radical independently selected from the groupconsisting of hydrogen and methyl radicals. The tocopherol wherein eachR is a methyl group is commonly referred to as a-tocopherol. Thetocopherol wherein the Rs at the and 8 positions of the molecule aremethyl radicals and R at the 7 position is a hydrogen radical is calledfi-tocopherol. The tocopherol wherein the Rs at the 7 and 8 positions ofthe molecule are methyl radicals and R at the 5 position is a hydrogenradical is fy-IOCOPhCl'Oi. Delta tocopherol is characterized by the R atthe 8 position being a methyl radical and Rs at the 5 and 7 positionsbeing hydrogen radicals. The tocopherol wherein the Rs at the 5 and 7positions of the molecule are methyl radicals and the R at the 8position is a hydrogen radical is zeta-tocopherol.

In 6-chromanol molecules wherein the R and R radicals are different, thecarbon atom at the 2 position is asymmetric and optical isomerismexists. Optical isomerism is a characteristic of the tocopherols whereinnot only is there an asymmetric carbon atom at the 2 position of themolecules but also there are asymmetric carbon atoms at the 4' and 8'positions of the side chain (R').

In the formula these asymmetric carbon atoms are indicated by asterisks.In naming these compounds, when it is desired herein to designate theparticular optical isomer involved, the position numbers of theasymmetric carbon atoms and the direction of optical rotation associatedwith each of these asymmetric carbon atoms are set out before the nameof the compound. Examples of this nomenclature are:2d,4'l,8d-a-tocopherol 21,4'd,8'l-,B-tocopherol 3,153,053 Patented Oct.13, 1964 Except for a few instances in the following disclosure, theregenerally is no need to designate the optical rotation efiect of eachasymmetric carbon atom of the molecules of the particular compoundinvolved. Generally, except for the few instances, all that is necessaryherein is to designate the net optical effect as is generally done inthe art, for example: d-a-tocopherol, dl-u-tocopherol (a racemic mixtureof optically active isomers, which mixture has no specific rotation).

This invention is based on the discovery that piperazine compoundsselected from the group consisting of piperazine and C-methyl andC-ethyl substituted piperazines react with 6-chromanols in the absenceof water to form crystallizable complexes. These complexes constitute anew class of compounds which are generically referred to herein as thepiperazine complexes of 6-chromanols. This discovery is particularlysignificant in view of the fact that attempts to form crystallizablecomplexes from some thirty other amines including N-methylpiperazine,morpholine, N-methyl morpholine and the like and either d-ocord-y-tocOpherol were not successful. This discovery is also significantin view of the fact that such chemicals as digitonin, desoxycholic acid,urea, oxalic acid and succinic acid, which are known complexing agentsfor other hydroxylic compounds, fail to form crystalline complexes withtocopherols.

This invention in one aspect comprises these piperazine complexes of6-chromanols. Generally, the molecular equivalent ratio of thepiperazine compound to the 6- chrornanol in these complexes is 1:2. Theyare represented by the formula:

R i R 0 N n n R R non 1W1 In" no i R n liquid to solid. As a class, theyhave a melting point and in the solid state are crystalline. Generally,they are highly soluble at 20 C. in the usual, inert, organic solventsbut of only limited solubility at -20 C. in these solvents. In thisregard, they exhibit selective or preferential crystallization fromcrystallization solvents containing in solution other crystallizablecompounds including other complexes of this invention. This selective orpreferential crystallization feature extends even to mixtures of twopiperazine complexes of 6-chromanols, which complexes differ from oneanother only in that the 6 chromanol portion of one complex is a simpleoptical isomer of the 6-chromanol portion of the other complex. Bysimple optical isomer is meant that the isomerism is only at oneasymmetric carbon atom position and not at more than one asymmetriccarbon atom position if more than one asymmetric carbon atoms arepresent. For example, two 6-chromanols which differ only in that one isa simple optical isomer of the other are:

2d,4'd,8'd-a-tocopherol 2l,4d,8'd-u-tocopherol As a matter of fact,these two 6-chromanols are the compounds which make up the racemicmixture of a-tocopherol, or dl-a-tocopherol, when such is synthesizedfrom natural phytol and trimethylhydroquinone. By selective orpreferential crystallization is meant that more of one crystallizablecompound than of another is crystallized from a solution comprising thetwo. Another interesting and useful property of these complexes is thatupon admixture with water they decompose to the original piperazines and6-chromanols. The compounds of this class in general have antioxidantproperties and, therefore, are useful as antioxidants for anhydrous,oxidizable substances such as, for example, fats and oils. Thepiperazine complexes of a-tocopherol, ti-tocopherol and 'y-tocopherolhave, in addition, both vitamin E activity to a substantial extent andanthelmintic activity. Hence, these particular complexes have utility inveterinary medicine.

This invention in another aspect comprises a process for making thesecomplexes. This process broadly comprises admixing a piperazine compoundselected from the group consisting of piperazine and C-methyl andC-ethyl substituted piperazines with a 6-chromanol in the absence ofwater. The expression C-methyl and C-ethyl substituted piperazinesrefers to piperazines having in their molecules the methyl and ethylsubstituents attached only to nuclear carbon atoms and not to nuclearnitrogen atoms. Typical examples of a piperazine compound are:

Piperazine Z-methylpiperazine Trans-2,S-dimethylpiperalineCis-Z,5-dimethylpiperazine 2,3,5 -trimethylpiperazine2,3,5,6-tetramethylpiperazine Other examples of a piperazine compoundinclude the C- ethyl substituted piperazines such as Z-ethylpiperazine,and the C-methyl, C-ethyl substituted piperazines such as2,S-dimethyl,6-diethylpiperazine. Typical examples of a 6-chromano1 are:

6-chromanol 2-methyl-6-chromanol 2,2,5,7,8-pentamethyl-6-chromanold-u-Tocopherol d-y-Tocopherol d-Zeta-tocopherol In preferred embodimentsof this process of this invention admixing of the piperazine compoundand the 6- chromanol takes place in a liquid medium which at thetemperature of admixture and crystallization temperature is chemicallyinert relative to the piperazine compound, the 6-chromanol and theresulting complex. It is preferred that the liquid medium be acrystallization solvent, that is, a solvent in which at admixingtemperature the complex is highly. soluble and at a differenttemperature, usually a lower temperature, the complex is substantiallyless soluble. Generally, under these admixing conditions, the piperazinecompound and 6-chromanol are also highly soluble at admixing temperaturein the liquid medium. A suitable liquid medium is acetone; Othersuitable organic solvents include hexane, esters, dialkyl ethers and thelike.

Inspecific embodiments of this process of this invention the piperazinecomplex of a o-chromanol, which is formed in and dissolved by theanhydrous liquid medium at admixing-temperature, is separated from the.liquid by lowering the temperature of the liquid medium or solu tion toa temperature at which substantial crystallization of the complex takesplace and then, after the desired extent of crystallization hasoccurred, removing the crystallized complex from the liquid medium. Suchremoval is by conventionalways such as, for example, filtration,decantation, centrifugation vand the like. In these embodiments of thisprocess of this invention a typical, preferred, admixing temperature isC. and a typical, preferred, crystallization temperature is 20 C.However, higher and lower admixingtemperatures and higher and lowercrystallization temperatures can be em ployed. In the case of. acetone apractical range of admixing temperatures is from about 0 to about 55 C.while a practical range of crystallization temperature is from about 40to about 0 C.

This invention in another aspect comprises a process for separating a6-chromanol and particularly a tocopherol from a mixture. This processis particularly useful in the purification of tocopherol products. Inthis regard the tocopherols are naturally occurring substances found invegetable oils. They are also synthesized by condensing phytol orisophytol with a compound of the group consisting of hydroquinone andmethyl substituted hydroquinones such as mono-, diandtrimethylhydroquinones. Whether produced from natural sources or bysynthesis, at some stage of their processing they are resent inso-called concentratesQ Natural tocopherol concentrates frequentlycontain glycerides, sterols, hydrocarbons and the like, which occur inthe vegetable oil along with the tocopherols. Synthetic tocopherolconcentrates usually contain by-products of the condensation reactionand unchanged starting materials or reactants. The final stages ofpurification of tocopherols from both types'of concentrates aredifiicultto carry out because the tocopherols are oils which do not crystallizereadily. Esters of tocopherols are sometimes solids at normaltemperatures and can be crystallized. Hence, crystallizable esters oftocopherols are sometimes employed to effect purification. However, thisrequires the step of esterification and work-up steps as well as thestep of saponification to recover the purified tocopherols. Under theconcepts of this invention, these steps are avoided.

In this aspect of the invention purification is effected by (1) admixingwith the concentrate in the absence of a significant concentration ofwater but in a solvent of the aforementioned kind at least onepiperazine compound selected from the group consisting of piperazine andC- methyl and C-etliyl substituted piperazines, (2) cooling theresulting solution to a temperature at which a substantial proportion ofthe resulting piperazine compound complex of a tocopherol crystallizes,(3) separating, after a substantial proportion of a piperazine compoundcomplex of a tocopherol has crystallized, the crystallized product fromthe solvent and (4) admixing the crystallized prod uct thus obtainedwith water, whereby decomposition of the complex or complexes takesplace. Usually it is preferred to wash the thus released tocopherol ortocopherols with Water to remove the released piperazine compound andthen dry the thus purified tocopherol or tocopherols product. It shouldbe noted that sterols and piperazines form highly insoluble, crystallinecomplexes. Hence, when treating according to this invention tocopherolconcentrates containing sterols, during the practice of the first twosteps, substantially all of the piperazine compound complexes of thesterols will rapidly crystallize out of solution before any significantcrystallization of the piperzine compound complexes of the tocopherol ortocopherols takes place. By removing this initial crop of crystalsbefore, any significant crystallization of the piperazine compoundcomplexes of the tocopherol or tocopherols takes place, separation ofsterols from tocopherols is thereby effected. In this regard, while thisaspect of this invention has been described relative to the purificationof tocopherol concentrates, it broadly encompasses the purification ofo-chromanol concentrates generally.

This invention has still another aspect in that it comprises a processfor separating a 6-chromanol from a homologous o-chromanol. A specificembodiment of this particular process, for example, involves theseparation of y-tocopherol from delta-tocopherol. The steps of thisprocess comprise admixing under substantially anhydrous conditions in asolvent of the aforementioned kind a piperazine compound and the mixtureof the two homologs. The temperature of the resulting solution isreduced to that whereat substantial crystallization takes place.Separation of the crystals from the solution is performed whencrystallization is substantially complete. The crystals predominate inthe complex of the piperazine compound and one of the 6-chromanols. Atthis point the crystals can be recrystallized as many times as desireduntil the desired degree of purity is achieved. The crystals are thenadmixed with Water to decompose the complex into the 6-chromanol and thepiperazine compound, and the 6-chromanol is separated from the water andthe piperazine compound.

This invention in still another aspect comprises a process forseparating a 6-chromanol from a simple optical isomer thereof. Such aprocess is useful for resolving a racemic mixture of simple opticalisomers having a 6- chromanol molecular structure. Indeed, a specificembodiment of this processcomprises the resolution of the synthetic ordl-Ot-tOCOPhGIO]. that is a racemic mixture of two simple opticalisomers, for example, such as in the case of the synthetic ordin-tocopherol product derived from natural phytol andtrimethylhydroquinone. Such a process is of value because synthetic ordl-u-tocopherol, a racemic mixture, has less vitamin E potency thannatural or d-a-tocopherol. This fact is reflected in The NationalFormulary, Eleventh Edition, on page 459, which sets out the followingequivalents, namely:

1 milligram of d-u-tocopherol=1.49 International Units of Vitamin E 1milligram of dl-ot-tocopherol=l.1 International Units of Vitamin E Thus,dZ-a-tocopherol has only about 73.8% of the biological activity of anequal quantity of d-a-tocopherol. The reason for this dilference inbiological activity is apparently the Lot-tocopherol content ofdl-ot-tocopherol. Apparently, l-ot-llOCOPhtilOl has less biologicalactivity than d-a-tocopherol. Hence, in order to obtain a vitamin Eproduct of maximum potency from dl-tx-tocopherol, it is necessary toresolve the mixture, to separate the d-oc-tO- copherol from thel-oz-tocopherol. One process heretofore proposed for carrying out such aseparation is disclosed in the US. patent, No. 2,215,398, to Karrer.This process, however, involves the step of esterification with anoptically active acid and, after separation of the esters has takenplace, the step of saponification to obtain the d-OL-tO- copherol. Underthe concepts of this invention these steps are avoided.

The process of this invention for resolving a synthetic ofdl-a-tocopherol that is a mixture of two simple optical isomers is basedon the fact that at the temperature of crystallization more of thepiperazine complex of the disomer is crystallized than the piperazinecomplex of the l-isomer. Thereafter, upon separating the crystals andmother liquor and subjecting the crystals to recrystallization and themother liquor to further crystallization conditions, the crystalfractions thereby obtained generaliy predominate in the piperazinecomplexes which are predominate in the solutions from which they arerecrystallized.

This process comprises a number of steps. The first step is admixing atleast one piperazine compound selected from the group consisting ofpiperazine and C- methyl and C-ethyl substituted piperazines with thedl-octocopherol in the absence of a substantial concentration of waterbut in a solvent of the aforementioned kind. The second step comprisescooling the resulting solution to a temperature at which a substantialproportion of the piperazine complex of d-ot-lLOCOPhGIOl crystallizes.The third step is separating after a substantial proportion of saidpiperazine complex has crystallized the crystallized product from thesolution. At this point it should be noted that because some of thepiperazine complex of the l-a-tocopherol also crystallizes at the sametime as the piperazine complex of d-a-tocopherol, although at a slowerrate, the crystallized product while rich in the piperazine complex ofthe d-ot-tocopherol also contains the piperazine complex of thelax-tocopherol.

Hence, in one embodiment of this process the next steps comprisedissolving the crystalline product in fresh sol.-

' vent or in solvent from a succeeding recrystallization step ifpracticed, cooling as in the second step, and then separating as in thethird step. This portion of the process can be repeated as many times asnecessary to obtain a crystalline product of the desired purity. Theproduct is then admixed with Water to decompose the complex and releasethe d-a-tocopherol.

On the other hand, in another embodiment of this process instead ofrecrystallization of the crystalline product, the product is admixedwith water and the released d-ottocopherol product, an oil, is treatedaccording to the first three steps. This procedure can be repeated asmany times as necessary to obtain the d-e-tocopherol product free to thedesired extent of l-lX-tOCOPhCl'Ol.

Of course, in other embodiments of this process both procedures can beemployed.

In all embodiments of this process it is preferred prac, tice to washthe d-ct-tocopherol product, particularly the final product, with waterto remove therefrom residual piperazine compound and then to dry thewashed product.

When it is desired to recover the lea-tocopherol in this resolutionprocess, several procedures can be employed. In one procedure the motherliquor in the first step, augmented if desired by the mother liquorsfrom the other crystallization steps, is maintained at a crystallizationtemperature until a substantial portion of the piperazine complex ofLee-tocopherol has crystallized, the crystalline product therebyobtained is separated from the solvent, and the product thereafteradmixed with water to decompose the complex and release thel-oc-tOCOPhel'Ol. In another procedure the solvent is removed as byvacuum evaporation fromthe mother liquor, whether augmented or not, andthe residue admixed with water to decompose the piperazine complex oflax-tocopherol and release the tocopherol.

This invention is further illustrated by the following examples ofvarious aspects thereof, which include specific embodiments of theinvention. This invention is not limited to these specific embodimentsunless otherwise indicated.

EXAMPLE 1 This example illustrates a complex of piperazine and2,2,5,7,8-pentamethyl-6-chromanol, and its preparation.

To a'solution of 2.2 grams (0.01 mole) of 2,2,5,7,8-pentamethyl-6-chromanol (which has a typical melting point of 9495 C.)in 10 milliliters of acetone at 20 (3., there is admixed 0.43 gram(0.005 mole) of piperazine. The resulting solution is cooled to 5 C. andheld at this temperature for 24 hours. A White crystalline solidresults. The mother liquor is decanted from the crystals and residualsolvent thereafter removed therefrom by distillation, whereby there isobtained a crystalline complex of piperazine and2,2,5,7,S-pentamethyl--chromanol. A typical yield of this product, is1.8 grams (0.003 mole). The product typically has a melting point of12l-122 C. and in ethanol-an ultraviolet absorption measurement ofli"... s) 124 The mole ratio of the 6-chromanol to the piperazinev inthe product is 2: 1.

EXAMPLE 2 Eifi (292 m )=71.9 is dissolved in acetone and admixed with asolution of 0.9 gram (0.01 mole) of piperazine in 10 milliliters ofacetone. The resulting solution is cooled to 20 C. and held at thistemperature for 24 hours, during which time a precipitate of crystallinesolids is formed. The mother liquor is decanted from the solids andresidual mother liquor removed therefrom by evaporation. The

product thus obtained is the complex of piperazine and d-oc-IOCOPhCI'Ol,the mole ratio of piperazine to tocopherol being 1:2. Theproducttypically has a melting point of 5254 C. and has in ethanol anultraviolet absorption value of r This example illustrates a complex ofd-ot-tocophcrol and 2-methylpiperazine, and its preparation.

To-a solution of 2 grams (0.0046 mole) of d-u-tocopherol in 8milliliters of acetone is added a solution of 0.23 gram (0.0023 mole)of'2-methylpiperazine in milliliters of acetone. The resulting solutionis cooled to 20 C. and held at this temperature for 24 hours. Duringthis time a White crystalline solid precipitates. The mother liquor isdecanted from the precipitate and oceluded solvent removed from theprecipitate by distillation, whereby a viscous oil is obtained whichsolidifies on cooling to 5 C. The solid product thus obtained-is thecomplex of Z-methylpiperazine and d-ot-tocopherol with the mole ratio of2-methylpiperazine to the tocopherol being 1:2. A typical yield of thisproduct is 1.5 grams (0.0016 mole). The product typically melts at 2224C. A typical ultraviolet absorption spectrum of the prod not in ethanolis tta... (291 mu) =65.7 EXAMPLE 4 This example illustrates thepreparation of a complex of d-a-tocopherol andtrans-2,S-dimethylpiperazine.

A solution of 2 grams (0.0046 mole) of d-a-tocoph erol in 8 millilitersof acetone and a solution of 0.26 gram (0.0023 mole) oftrans-2,S-dimethylpiperazine in milliliters of acetone are admixed. Theresulting solution is concentrated to about 10 milliliters byevaporation under a stream of nitrogen. The concentrate is then cooledto 20 C., and held at this temperature for 24 hours, whereby a white,crystalline solid is precipitated. The mother liquor is decanted fromthe precipitate and occluded solvent removed by distillation. Theresidue is the desired product, the complex of d-a-tocopherol andtrans-2,S-dimethylpiperazine with the mole ratio of the tocopherol tothe piperazine being. 2:1. This product typically melts at 24-26 C. butresolidilies on cooling under a stream of cold tap water. The product inethanol typically has an ultraviolet absorption value of li's. u)=65EXAMPLE 5 This example illustrates the preparation of a complex ofd-y-tocopherol and piperazine.

An acetone solution of 4.2 grams (0.01 mole) of sub stantially pured-y-tocopherol obtained from soybean oil (having in ethanol anultraviolet absorption value of li... u)=

is admixed with a solution of 0.43 gram (0.005 mole) El? (296 m )=84.5EXAMPLE 6 This example illustrates the preparation of a crystallinecomplex from al-zeta-tocopherol and piperazine.

dl-Zeta-tocopherol is synthesized, as described in Nature 179, 418(1957), from 2,6-dimethyl hydroquinone and isophytol, and purified bychromatography. 7.68 grams (0.018 mole) of the purified(il-zeta-tocopherol is dissolved in 40 milliliters of acetone containing0.79 gram (0.009 mole) of piperazine. Upon cooling the solution thusobtained to 20 C. and holding the solution at this temperature for 24hours a white crystalline precipitate results. The precipitate isfiltered ofi and dried under vacuum. Typically, there is therebyobtained 5.6 grams of a crystalline solid having a melting point of 3942 C. Recrystallization of the solid from three volumes of acetone givestypically'4.26 grams (0.005 mole) of product. This product typically hasa melting point of 40-42 C. It comprises the piperazine complexes ofdand l-zeta-tocopherol with the mole ratio of the tocoph erol topiperazine in each complex being 2:1.

EXAMPLE 7 This example illustrates the utility as an antioxidant of thecomplex of d-a-tocopherol and piperazine, which complex is preparedacocrding to Example 2.

One liter samples of diethyl ether, one sample containing no additiveand the other samples containing in solution the additives indicated inthe following Table I at the indicated concentrations are prepared andstored in stoppered brown bottles in the dark at 20 C. for 60 days. Atthe end of this time aliquot portions of the samples are taken out andassayed for peroxides. Typically little or no peroxides are found in anyof the samples. Thereafter, the bottles are exposed to ordinary light asby being placed on an open shelf in a normally light room and after 11days and 25 days of this exposure aliquot portions These typical datademonstrate that the complex of (1-0:- tocopherol and piperazine is aneffective antioxidant for diethyl ether. Moreover, these typical dataindicate that the complex of d-a-tocopherol and piperazine has anantioxidant effect that is substantially greater than the antioxidanteffects of either piperazine or d-wtocopherol at slightly greatermolecular equivalent concentrations and that this effect issubstantially greater than the sum of the effects of piperazine andd-a-tocopherol when each effect is considered as the multiplicationfactor by which the per oxide value of the control or sample without anadditive exceeds the peroxide value of the corresponding sample Withadditive.

EXAMPLE 8 This example illustrates the purification of a substantiallyanhydrous, natural d-a-tocopherol concentrate according to a process ofthis invention.

9.39 grams of a d-ct-tocopherol concentrate, obtained from soybean oil,containing about by weight of d-wtocopherol as determined by infraredassay and typically being reddish in color is dissolved in 20milliliters of acetone. To this solution is added a solution of 0.9 gramof piperazine in 10 milliliters of acetone. The resulting solution iscooled to 20 C. and held at this temperature for 24 hours. During thistime a crystalline solid precipitates. The mother liquor is decantedfrom the precipitated crystalline solids and the solids are dis- Efi(292 m =71.9 EXAMPLE 9 This example illustrates the purificationaccording to a process of this invention of a synthetic a-tocopherolconcentrate.

15 grams of a substantially anhydrous, synthetic a-tocopherolconcentrate (a typical ultraviolet absorption measurement in ethanol isste (292 m,.=51.1

while a typical Emmerie-Engel assay is 71.6% by weight oc-tocopherol) isdissolved in 50 milliliters of acetone at 20 C. To the solution thusobtained 1 gram of piperazine is admixed therewith and the mixturewarmed slightly to efiect solution of the piperazine. The resulting solution is then cooled to 20 C., held at this temperature for 24 hours,cooled further to 40 C. and held at this temperature for approximatelylhour. This results in a precipitate of crystalline solids. Theseprecipitated crystalline solids are separated from the mother liquor byfiltration followed by washing with cold acetone. v The crystals aredissolved in diethyl ether and the resulting solution washed severaltimes with Water to decompose the complexes and remove the piperazine.The ether solution is then dried over anhydrous sodium sulfate,

tered and the ether removed by distillation. The product therebyobtained, an oil, is an enriched, a a-tocopherol concentrate. A typicalyield of the product is 9.0 grams. A typical ultraviolet absorptionvalue of the product in ethanol is Etta... my) =69.9

An Emmerie-Engel assay of the residue gives a typical value of 47% byweight Ot-lOCOPl'EI'Ol.

EXAMPLE This example illustrates the purification according to a processof thisinvention of a d-y-tocopherol concentrate.

44 grams of a substantially anhydrous, d-' -tocopherol concentrateobtained from soybean oil, which concentrate typically is a red oilhaving in ethanol an ultraviolet absorption value of and containing 81%by weight d- -toco-pherol mixed with 10-15% by Weight d-a-tocopherol andd-delta-tocopherol as determined by infrared assay is dissolved in .150

milliliters of acetone. To the resulting solution is admixed at 20 C. asolution of 4.3 grams of piperazine in 150 milliliters of acetone. Thesolution thus obtained is cooled to 20 C. and held at this temperaturefor 24 hours. During this time a precipitate of crystalline solidsforms. The mother liquor is decanted from the crystalline solids and thesolids washed with a 50 milliliter portion of cold acetone. A sample ofthe solids in the absence of acetone hasa typical melting point'of 55-58 C; The solids are dissolved in 50 milliliters of petroleum ether andthe resulting solution washed in succession with three 200 milliliterportions of water. After drying the solutionover anhydrous sodiumsulfate and removing the petroleum ether by evaporation there isobtained a light yellow oil, which oil is a purified d-v-tocopherolconcentrate. A typical yield of the oil is 25 grams.

The light yellow oil is admixed at 20 C. with 2.5 grams of piperazinedissolved in milliliters of acetone. The temperature of the resultingsolution is lowered to -20 C. and maintained thereat for 24 hours,wherey a crystalline precipitate forms. The mother liquor is decantedfrom the precipitate and the precipitate washed with 50 milliliters ofcold acetone. The Washed precipitate is dissolved in 50 milliliters ofpetroleum ether and the solution thus formed is washed three times with200 milliliter portions of water. The washed petroleum ether solution isdried over anhydrous sodium sulfate and the petroleum ether then removedby evaporation. There is thereby obtained an oil which typically byinfrared assay is found to be substantially pure d-v-tocopherol andwhich. in ethanol has a typical ultraviolet absorption value of ll... Atypical yield of the oil under these conditions is 16.5 grams.

EXAMPLE 11 This example illustrates the separation according to aprocess of this invention of a d y-tocopherol concentrate from a mixtureof dy-tocopherol and d-deltatocopherol.

12 grams of a tocopherol concentrate containing a mixture ofd-y-tocopherol and d-delta-t0c0pl1er0l at typical concentrations of 34and 33% by weight, respectively, are dissolved in 20 milliliters ofacetone. To this solution there is admixed at 20 C. a solution of 0.8gram of piperazine in 20 milliliters of acetone. The resulting solutionis cooled to '20 C. and held at this temperature for 24 hours. Duringthis period of time'a crop of crystals forms in the solution. The motherliquor is decanted from the crystals and the crystals are then dissolvedin diethyl ether. The ether solution is washed several times with water,whereby the complexes present are decomposed and the released piperazineremoved.

The washed ether solution is then dried over anhydrous sodium sulfateand the ether removed by evaporation, leaving a residue of oil. Atypical yield of the oil is 4.6 grams. Infrared absorption analysisofthis oil shows that the Weight ratio of d-y-tocopherol tod-delta-tocopherol is typically 2.5 :l.

Theoil is dissolved in 20 milliliters of acetone. To this solution thereis admixed at 20 C. a solution of 0.4 gram of piperazine and 10milliliters of acetone. The resulting solution is cooled to -20 C. andheld at this temperature for 24 hours. During this time a crop ofcrystals forms in the solution. The mother liquor is decanted from thecrystals and the crystals are dissolved in ethyl ether. The ethersolution is washed several times with water. The washed other solutionis thendried over anhydrous sodium sulfate and the ether removed byevaporation. The product thus obtained is an oil, a typical yield being2 grams. A typical infrared absorption analysis of this productshows'd-v-tocopherol at a concentration of 63% erol at a concentrationof only 7% by Weight.

EXAMPLE 12 by weight and d-delta-toco-phby weight of long chainhydrocarbons) with 6.6 grams of pure d-rx-tocopherol, an oil. Theresulting mixture is dissolved at 20 C. in 20 milliliters of acetone,giving a concentrate solution.

0.69 gram of piperazine is dissolved at 20 C. in milliliters of acetone,giving a piperazine solution.

The piperazine solution is admixed at 20 C. with the concentratesolution. The temperature of the resulting solution is lowered to 0 C.and maintained at this temperature for 1 hour.

During this period of time a precipitate of solids forms in thesolution. These solids are removed from the solution by filtration,washed with cold acetone and dried. These solids are piperazinecomplexes of the sterols. A typical melting point of the solids is147-152 C. A typical yield of the solids under these conditions is 0.79gram, which indicates that substantially all of the sterols have beenremoved from the solution.

The solution after filtration of the solids therefrom is maintained at 0C. for 24 hours. During this period of tine another precipitate ofsolids forms. These solids are removed from the mother liquor byfiltration, washed with cold acetone and dried. These solids are thepiper azine complex of d-a-tocopherol. A typical melting point of thesolids thus obtained is 5254 C. 'A typical yield of the solids is 3.5grams. These solids'are washed with water whereupon the complex isdecomposed to give the d-ot-tocopherol oil substantially free ofsterols.

EXAMPLE 13 This example illustrates the partial resolution ofdl-cxtocopherol synthesized from natural phytol andtnimethylhydroquinone.

In this example reference is frequently made to the specific rotation [Mof oxidation product. The oxidation product in each case is the productobtained by admixing the analytical sample of the u-tocopherol involvedwith an aqueous alkaline solution of potassium ferricyanide, separatingthe resulting oil layer from the aqueous layer and then drying the oil.Measurement of the optical rotation of'the oil is then obtained by theusual procedure. The significance of the specific rotation of oxidationproduct is that in the case of a d-utocopherol [a] of oxidationproduct=+35 while in the case of cil-a-tocopherol [a] of oxidation prodm0". Hence, a value between the limits of 0 and +35 is a measure of thedegree of resolution obtained.

4.3 grams of a dl-ot-tocopherol product synthesized from natural phytoland trimethylhydroquinone, which product typically has in ethanol anultraviolet absorption value of and [a] of oxidation produot=0%, isdissolved in milliliters of acetone. To this solution is admixed at 20C. a solution of 0.11 gram of piperazine in 10 milliliters of acetone.The resulting solution is cooled to 20 C. and maintained at thistemperature for 15 hours. During this period of time a precipitate ofcrystalline solids forms. The precipitate is separated from the motherliquor by filtration and residual solvent removed by evaporation. Atypical yield of the solids is 0.4 gram. A typical melting point of thesolids is 50-51 C.

The solids are dissolved in petroleum ether and then washed with waterto decompose the complexes and remove the piperazine. The petroleumother solution is then dried over anhydrous sodium sulfate and thepetroleum ether removed by evaporation. The residue is an oil. A typicalyield of the oil is 0.36 gram. A typical ultraviolet absorptionmeasurement on the oil in ethanol gives Ela (292 Inu =76 Typically, M1of the oxidation product=+ 17. This value indicates that the oil has a2d,4'd,8'd-ottocopherol concentration of 83% by weight.

The motherliqiror after removal of the precipitate or first crop ofcrystals is admixed at 20 C. with 0.11 gram of piperazine and recooledto =-20 C. This temperature is maintained for 24 hours. During thisperiod of time a second crop of crystals forms. The second crop ofcrystals is separated from the mother liquor by filtration and residualsolvent removal by evaporation. A typical yield of crystals in this stepis 0.18 gram.

The crystals are dissolved in petroleum ether and then washed withwater. The petroleum ether solution is then dried over anhydrous sodiumsulfate and the petroleum ether removed by evaporation. The residueagain is an oil which the [0c] of the oxidation product indicates has a2d,4'd,8'd-a-tocopherol concentration typically of 81% by weight.

After the foregoing separation of the second crop of crystals from themother liquor, the petroleum other is removed by evaporation from themother liquor, leaving an oil. This product is a 2l,4d8'd-a-tocopherolconcentrate. Typically, [a] of the oxidation product .03".

EXAMPLE 14 This example illustrates the separation according to aprocess of this invention of a substantially pure 2d,4d,8'da-tocopherolfrom a dl-a-tocopherol such as that obtained by synthesis from naturalphytol and trimethylhydroquinone.

Reference is frequently made in this example also to the specificrotation M1 of oxidation product. For an explanation of the meaning andsignificance of this, see the preceding Example 12.

To 46 grams of' a dl-a-tocopherol synthesized from natural phytol andtrimethylhydroquinone and purified by chromatography, typically givingin ethanol an ultraviolet absorption value of is admixed at 20 C. asolution of 4.5 grams of piperazine and milliliters of acetone. Theresulting solution is cooled to 20 C. and held at this temperature for24 hours. During this period of time a precipitate of crys tals isformed. The precipitate of crystals is separated from the mother liquorby filtration and by evaporation of residual solvent. A typical yield ofthe solid product is 35.1 grams. A sample of this product taken up inpetroleum ether, washed with water and then solvent evaporated hastypically a specific rotation [a] of oxidation product=+2'.01-", whichindicates some resolution has already occurred.

The solid product is then subjected to six successive crystallizationsteps. In each step the crystals are dissolved at 20 C. in freshacetone, the resulting solution then cooled to 20 C. and held at thistemperature for 24 hours, mother liquor removed, first by decantationand then by evaporation, from the resulting crystals. The crystalproduct is then weighed and a sample is removed for analysis. The samplein each case is prepared for analysis by dissolving it in petroleumether, washing with water to decompose the complexes and removing thepiperazine and then removing the solvent by evaporation to give ana-tocopherol oil. Typical results of this successive crystallizationprocedure are set out in the following Table II.

Table II p Volume in Weight in [0419 of Crystallization Step MillilitersGrams of Oxidation of Acetone Crystalline Product Employed Product 1 ofproduct is 3.29 grams. A typical ultraviolet absorption value of theproduct-in ethanol is Acetylation of a portion of the product gives a2d,4d, 8'd- OL-tOCOPhCl'Y]. acetate composition which typically has aspecific rotation of [m] -=+2.78" and in ethanol an ultravioletabsorption value of Eifi (284 mp) =42.6 EXAMPLE 15 This exampleillustrates a process according to this invention for obtaining a 21,4'03, Sd-a-tocopherol concentrate from dl-a-tocopherol synthesized fromnatural phytol and trimethylhydroquinone.

The steps of Example 14 are followed down through the initialcrystallization step which includes the separation by filtration of theprecipitate of crystals from the mother liquor. The solvent is removedby evaporation from the filtrate or mother liquor, leaving a residue ofsolids. These solids are dissolved in petroleum ether and the resultingsolution washed with water to decompose the complexes and remove thepiperazine. The washed solution is dried over anhydrous sodium sulfateand the petroleum ether removed by evaporation. There results, thereby,a crude concentrate of 21, 4d,8d-ot-tocopherol. A typical yield of thisconcentrate is 7.5 grams. A typical specific rotation [u] of theoxidation product=6.

This crude concentrate is admixed at 20 C. with 0.46 gram of piperazinedissolved in 75 milliliters of acetone. The resulting solution is cooledto -20 C. and maintained at this temperature for 24 hours, resulting ina crop of crystals.

The mother liquor is separated from this crop of crystals by filtrationand then by evaporation. A typical yield of crystals is 1.7 grams. Asample of the crystals is washed with water to release the tocopheroland analyzed. Typically, the specific rotation M1 of the oxidationproduct=-11.5. The crystals are dissolved in 8.5 milliliters of freshacetone at 20 C. The resulting solution is then cooled to 20 C. andmaintained at this temperature for 24 hours whereby a crop of crystalsis obtained. The mother liquor is decanted from the crystals and thenevaporated therefrom. The crystals are dissolved in diethyl ether,washed with water to decompose the complexes and remove the releasedpiperazine. The washed diethyl ether solution is dried over anhydroussodium sulfate and the solvent removed by evaporation. Thus there isobtained a 2l, 4'd,8d-a-tocopherol concentrate. A typical yield is 1.1grams. A typical specific rotation la] Q of the oxidation product is15.20, there by indicating the concentration of 2l,4'd,8'd-m-tocopherolis 73.3% by weight.

Thus, there are provided crystalline complexes of 6- chromanols andpiperazines. In addition, there is provided a method for readilyresolving dl-a-tocopherol that is a racemic mixture of two simpleoptical isomers. Moreover, there is provided a process for separatingone 6-chromanol from another and for purifying 6-chroma- 11015.

Other advantages, benefits and embodiments will be apparent to those inthe exercise of ordinary skill in the art after reading the foregoingdisclosure. In this regard, while this invention has been described inconsiderable detail relative to certain specific embodiments thereof,variations and modifications of these embodiments can be effected withinthe spirit and scope of the invention as disclosed and claimed.

14* This application is a division of the US. patent application ofCharles D. Robeson et al., Serial No. 190,249, filed April 26, 1962, forChemistry of 6-Chromanols.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A process for purifying a substantially anhydrous, concentrate of aG-chromanol which comprises: admixing with said concentrate asubstantially anhydrous crystallization solvent and a piperazinecompound selected from the group consisting of piperazine and C-methyland C-ethyl substituted piperazines, whereby there is formed a solutioncontaining a complex of said piperazine compound and G-chromanol;changing the temperature of said solution to a temperature at which thesolubility of said complex is substantially less, whereby crystals ofsaid complex are for-med; separating said crystals from said solution;admixing said crystals with water, whereby said complex decomposes tosaid 6-chromanol and said piperazine compound; and separating said6-chromanol from said Water and said piperazine compound.

2. A process for purifying a substantially anhydrous, concentrate of atocopherol which comprises: admixing with said concentrate asubstantially anhydrous crystallization solvent. and a piperazinecompound selected from the group consisting of piperazine and C-methyland C- ethyl substituted piperazines, whereby there is'formed a solutioncontaining a complex of said piperazine compound and tocopherol;changing thetemperature of said solution to a temperature at which thesolubility of said complex is substantially less, whereby crystals ofsaid complex are formed; separating said crystals from said solution;admixing said crystals with water, whereby said complex decomposes tosaid tocopherol and said piperazine compound; and separating saidtocopherol from said water and said piperazine compound.

3. A process for purifying a substantially anhydrous, concentrate ofd-a-tocopherol which comprises: admixing with said concentrate asubstantially anhydrous crystallization solvent and a piperazinecompound selected from the group consisting of piperazine and C-methyland C- ethyl substituted piperazines, whereby there is formed a solutioncontaining a complex of said piperazine compound and d-a-tocopherol;changing the temperature of said solution to a temperature at which thesolubility of said complex is substantially less, whereby crystals ofsaid complex are formed; separating said crystals from said solution;admixing said crystals with water, whereby said complex decompose tosaid d-m-tocopherol and said piperazine compound; and separating saidd-a-tocopherol from said water and said piperazine compound.

4. A process for purifying a substantially anhydrous, concentrate ofd-y-tocopherol which comprises: admixing with said concentrate asubstantially anhydrous crystallization solvent and a piperazinecompound selected from the group consisting of piperazine and C-methyland C-ethyl substituted piperazines, whereby there is formed a solutioncontaining a complex of said piperazine compound and d-y-tocopherol;changing the temperature of said solution to a temperature at which thesolubility of said complex is substantially less, whereby crystals ofsaid complex are formed; separating said crystals from said solution;admixing said crystals with water, whereby said complex decomposes tosaid d-y-tocopherol and said piperazine compound; and separating saidd-y-tocopherol from said water and said piperazine compound.

5. A process for separating a 6-chr0manol from a homologous 6-chromanolwhich comprises: admixing with said 6-chromanol and homologous6-chromanol under substantially anhydrous conditions a crystallizationsolvent and a piperazine compound selected from the group consisting ofpiperazine and C-methyl and C-ethyl substituted piperazines, wherebythere is formed a solution containing the complexes of said piperazinecompound and said 6-chromanols; changing the temperature of saidsolution to a temperature at which the solubility of the complex of saidpiperazine compound and one of said 6-chromanols is substantially less,whereby crystals of said complex are formed; separating said crystalsfrom said solution; ultimately admixing at least a portion of saidcrystals with water, whereby said complex decomposes to said one of saido-chromanols and said piperazine compound; and separating one of said6-chromanols from said Water and said piperazine compound.

6. A process for separating -tocopherol from deltatocopherol whichcomprises: admixing with said 'y-tO- copherol and delta-tocopherol undersubstantially anhydrous conditions a crystallization solvent and apiperazine compound selected from the group consisting of piperazine andC-methyl and C-ethyl substituted piperazines, whereby there is formed asolution containing the complexes of said piperazine compound and saidtocopherols; changing the temperature of said solution to a temperatureat which the solubility of the complex of said piperazine compound and'y-tocopherol is substantially less, whereby crystals of said complexare formed; separating said'crystals from said solution; ultimatelyadmixing at least a portion of said crystals with water, whereby saidcomplex decomposes to said piperazine compound and y-tocopherolg andseparating said 'y-tocopherol from said water and said piperazinecompound.

7. A process for separating an optically active 6-chromanol from asimple optical isomer thereof which comprises: admixing with saidoptically active 6-chrornanol and simple optical isomer thereof undersubstantially anhydrous conditions a crystallization solvent and apiperazine compound selected from the group consisting of piperazine andC-methyl and C-ethyl substituted piperazines, whereby there isformcd asolution containing the complexes of said piperazine compound and saidoptically active 6-chromanol and said optical isomer thereof; changingthe temperature of said solution to a temperature at which thesolubility of the complex of said piperal6 zine compound and one or"said optically active 6-chromanol and said simple optical isomer thereofis substantially less, whereby crystals of said complex are formed;separating said crystals from said solution; ultimately admixing atleast a portion of said crystals with water, whereby said complexdecomposes tosaid one of said optically active 6-chroman0l and saidsimple optical isomer thereof and said piperazine compound; andseparating one of said optically active '6-chromanol and said Simpleoptical isomer thereof from said water and said piperazine compound.

8. A process for separating 2d,4'd,8d-at-tocopherol from2l,4'd,8'd-u-tocopherol which comprises: admixing with said2d,4d,8'd-a-tocopherol and 2l,4'd,8'd-u-tocopherol under substantiallyanhydrous conditions a crystallization solvent and a piperazine compoundselected from the group consisting of piperazine and C-methyl andC-ethyl substituted piperazines, whereby there is formed a solutioncontaining the complexes of said piperazine compound and saidtocopherols; changing the temperature of said solution to a temperatureat which the solubility of the complex of said piperazine compound and2d,4d,8'd-u-tocopherol is substantially less, whereby crystals of saidcomplex are formed; separating said crystals from said solution;ultimately admixing at least a portion of said crystals with water,whereby said complex decomposes to saidpiperazine compound and2d,4'd,8'da-tocopherol and separating said 2d,4'd-8'd-a-tocopherol fromsaid water and said piperazine compound.

Green et al. July 11, 1961

1. A PROCESS FOR PURIFYING A SUBSTANTALLY ANHYDROUS, CONCENTRATE OF A6-CHROMANOL WHICH COMPRISES: ADMIXING WITH SAID CONCENTRATE ASUBSTANTIALLY ANHYDROUS CRYSTALLIZATION SOLVENT AND A PIPERAZINECOMPOUND SELECTED FROM THE GROUP CONSISTING OF PIPERAZINE AND C-METHYLAND C-ETHYL SUBSTITUTED PIPERAZINES, WHEREBY THEREIS FORMED A SOLUTIONCONTAINING A COMPLEX OF SAID PIPERAZINE COMPOUND AND 6-CHROMANOL;CHANGING THE TEMPERATURE OF SAID SOLUTION TO A TEMPERATURE AT WHICH THESOLUBILITY OF SAID COMPLEX IS SUBSTANTIALLY LESS, WHEREBY CRYSTALS OFSAID COMPLEX ARE FORMED; SEPARATING SAID CRYSTALS FROM SAID SOLUTION;ADMIXING SAID CRYSTALS WITH WATER, WHEREBY SAID COMPLEX DECOMPOSES TOSAID 6-CHROMANOL AND SAID PIPERAZINE COMPOUND; AND SEPARATING SAID6-CHROMANOL FROM SAID WATER AND SAID PIPERAZINE COMPOUND.